The major objective of this proposal is to investigate therapeutic approaches for inherited photoreceptor degeneration. Murine models with defined genetic defects simulating human photoreceptor degeneration will serve as the primary experimental system with which to study the efficacy of replacement gene therapies. The gene defects to be studied are selected based on greater clinical significance as they cause severe forms of the disease and/or affect a large proportion of patients with photoreceptor degeneration. These studies will seek direct evidence that the gene replacement therapy will halt photoreceptor cell death even after such a process has begun in the retina, and will allow regrowth of photoreceptor outer segments and restoration of photoreceptor function. Issues relating to the efficient targeting of rod and cone photoreceptors and proof of efficacy with human gene constructs will be addressed. The outcomes of this research should provide the critical information necessary for a transition from genetic studies in animal models to future clinical applications of replacement gene therapy in patients with photoreceptor degeneration. [unreadable] [unreadable] [unreadable]